This invention relates to novel indole compounds useful for inflammatory diseases.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
Indole type sPLA2 inhibitors having gyloxylamide, acetamide and hydrazide substituents are described in U.S. Pat. Nos. 5,654,326; 5,684,034; and 5,578,634 respectively.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as sepsis or rheumatoid arthritis.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention is a novel indole compound to inhibit mammalian sPLA2 mediated release of fatty acids.
This invention is also a novel class of indole having potent and selective effectiveness as inhibitors of mammalian sPLA2.
This invention is also a indole compound in the treatment of Inflammatory Diseases.
This invention is also a pharmaceutical composition containing the indole of the invention.
This invention is also a method of preventing and treating Inflammatory Diseases in mammals by administration of a therapeutically effective amount of the indole of the invention.
This invention is also the indole compounds of the invention or compositions comprising the compounds of the invention as active ingredient for use as a medicament in the treatment of Inflammatory Diseases.
Definitions
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, asthma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term, xe2x80x9cindole nucleusxe2x80x9d refers to a nucleus (having numbered positions)with the structural formula (X): 
The indole compounds of the invention employ certain defining terms as follows:
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d means an organic group containing only carbon and hydrogen.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo. The term, heterocyclic radical, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1,2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and quinoxalinyl.
The term, xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a): 
where n is a number from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals suitable for substitution at positions 4,5,6 and/or 7 of the indole nucleus and on other nucleus substituents (as hereinafter described for Formula I), and radicals suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C8 alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C2-C8 haloalkoxy, C1-C8 haloalkylsulfonyl, C2-C8 haloalkyl, C1-C8 hydroxyalkyl, xe2x80x94C(O)O(C1-C8 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C8 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where R is C1-C8 alkyl and n is from 1 to 8.
The term, xe2x80x9corganic substituentxe2x80x9d refers to a monovalent radical consisting of carbon and hydrogen with or without oxygen, nitrogen, sulfur, halogen, or other elements. Illustrative organic substituents are C1-C8 alkyl, aryl, C7-C14 aralkyl, C7-C14 alkaryl, C3-C8 cycloalkyl, C1-C8 alkoxyalkyl and these groups substitued with halogen, xe2x80x94CF3, xe2x80x94OH, C1-C8 alkyl, amino, carbonyl, and xe2x80x94CN.
The term, xe2x80x9cacylsulfonamide groupxe2x80x9d is an (acidic group) represented by the formula: 
where R81 is an organic substituent or the radical xe2x80x94CF3.
The term, xe2x80x9c(acidic group)xe2x80x9d means an organic group which when attached to an indole nucleus, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an (acidic group) are the following:
-5-tetrazolyl,
xe2x80x94SO3H, 
where n is 1 to 8, R80 is a metal or C1-C8 and R81 is an organic substituent or xe2x80x94CF3.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the 4 or 5 position of the indole nucleus to an acidic group in the general relationship: 
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 4 or 5 position of the indole nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9caminexe2x80x9d, includes primary, secondary and tertiary amines.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human.
The term, xe2x80x9calkylene chain of 1 or 2 carbon atomsxe2x80x9d refers to the divalent radicals, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94.
The term, xe2x80x9cgroup containing 1 to 4 non-hydrogen atomsxe2x80x9d refers to relatively small groups which form substituents at the 2 position of the indole nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, and xe2x80x94CHxe2x95x90CH2.
The term xe2x80x9cureidoxe2x80x9d means the radical, xe2x80x94NHxe2x80x94C(O)xe2x80x94NH2.
The term xe2x80x9cthioureidoxe2x80x9d means the radical xe2x80x94NHxe2x80x94C(S)xe2x80x94NH2.
The term xe2x80x9cspiro[5.5]undecanylxe2x80x9d refers to the group represented by the formula; 
The indole Compounds of the Invention:
The compounds of the invention have the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
wherein;
R1 is selected from groups (a), (b) and (c) wherein;
(a) is C7-C20 alkyl, C7-C20 haloalkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L1)xe2x80x94R11; where, xe2x80x94(L1)xe2x80x94 is a divalent linking group of 1 to 8 atoms and where R11 is a group selected from (a) or (b);
R2 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;
R3 is xe2x80x94(L3)xe2x80x94 Z, where xe2x80x94(L3)xe2x80x94 is a divalent linker group selected from a bond or a divalent group selected from: 
and Z is selected from a group represented by the formulae, 
wherein, X is oxygen or sulfur; Y is xe2x80x94NH2, C1-C4 alkyl, xe2x80x94CF3, xe2x80x94CONH2 or xe2x80x94CH2Z where Z is F, Cl, Br, or I;
R4 and R5 are independently selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)-(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 8, provided, that at least one of R4 and R5 must be the group, xe2x80x94(La)xe2x80x94 (acidic group);
R6 and R7 are selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s).
Preferred Subgroups of Compounds of Formula (I)
I. Preferred R1 Substituents
A preferred subclass of compounds of formula (I) wherein for R1 the divalent linking group xe2x80x94(L1)xe2x80x94 are those corresponding to the formulae (VIIa), (VIIb), (VIIc), (VIId), (VIIe), and (VIIf): 
where Q1 is a bond or any of the divalent groups (VIIa), (VIIb), (VIIc), (VIId), (VIIe), and (VIIf) and each R10 is independently hydrogen, C1-8 alkyl, C1-8 haloalkyl or C1-8 alkoxy.
Particularly preferred as the linking group xe2x80x94(L1)xe2x80x94 of R1 is a divalent alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94 or xe2x80x94(CH2xe2x80x94CH2)xe2x80x94.
The preferred group for R11 is a substituted or unsubstituted group selected from the group consisting of C5-C14 cycloalkyl, C5-C14 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a); 
where n is a number from 1 to 8.
Particularly preferred are compounds wherein for R1 the combined group xe2x80x94(L1)xe2x80x94R11 is selected from the group consisting of 
where R12 is a radical independently selected from halo, C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), xe2x80x94Oxe2x80x94(C1-C8 alkyl) and C1-C8haloalkyl where t is a number from 0 to 5 and u is a number from 0 to 4.
II. Preferred R2 Substituents
R2 is preferably selected from the group consisting of hydrogen, C1-C4 alkyl, C2-C4 alkenyl, xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94Sxe2x80x94(C1-C3 alkyl), xe2x80x94C3-C4 cycloalkyl xe2x80x94CF3, halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO3. Particularly preferred R2 groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3.
III. Preferred R3 Substituents
A preferred subclass of compounds of formula (I) are those wherein X is oxygen.
Another preferred subclass of compounds of formula (I) are those wherein Z is a ureido group. 
Most preferred are compounds of formula (I) wherein R3 is the ureido group. For the group R3 it is preferred that the linking group xe2x80x94(L3)xe2x80x94 be a bond.
IV. Preferred R4 Substituents
Another preferred subclass of compounds of formula (I) are those wherein R4 is a substituent having an acid linker with an acid linker length of 2 or 3 and the acid linker group, xe2x80x94(L4)xe2x80x94, for R4 is selected from a group represented by the formula; 
where Q2 is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94, and xe2x80x94Sxe2x80x94, and each R40 is independently selected from hydrogen, C1-C8 alkyl, aryl, C1-C8 alkaryl, C1-C8 alkoxy, aralkyl, and halo. Most preferred are compounds where the acid linker, xe2x80x94(L4)xe2x80x94, for R4 is selected from the specific groups; 
where R40 is hydrogen or C1-C8 alkyl. Preferred as the (acidic group) in the group R4 are acidic groups selected from:
-5-tetrazolyl,
xe2x80x94SO3H, 
where R80 is a metal or C1-C8 and R81 is an organic substituent or xe2x80x94CF3. A salt or a prodrug derivatives of the (acidic group) is also a suitable substituent.
Particularly preferred are acidic groups selected from:
xe2x80x94CO2H,
xe2x80x94SO3H,
xe2x80x94P(O)(OH)2 
or salt, and prodrug (e.g., ester, amide) derivatives thereof.
V. Preferred R5 Substituents
The most preferred acidic group in the compounds of the invention is a carboxylic acid group, xe2x80x94CO2H. Preferred acid linker, xe2x80x94(La)xe2x80x94, for R5 is selected from of; 
wherein R54, R55, R56 and R57 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, or halo.
VI. Preferred (Acidic Group) for R4 and/or R5 Substitutions
At least one of R4 and R5 must be the group, xe2x80x94(La)-(acidic group). The preferred (acidic group) on the group xe2x80x94(La)-(acidic group) of R4 or R5 is selected from xe2x80x94CO2H, xe2x80x94SO3H, or xe2x80x94P(O)(OH)2. In addition, it is preferred that only one R4 or R5 substituents be the group, xe2x80x94(La)-(acidic group). Most preferred is that the R4 substituent be the group, xe2x80x94(La)-(acidic group). The most preferred (acidic group) is carboxyl.
V. Preferred R6 Substituents
Another preferred subclass of compounds of formula (I) are those wherein for R6 the non-interfering substituent is methyl, ethyl, propyl, isopropyl, thiomethyl, xe2x80x94O-methyl, C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and carbonyl; where R is C1-C8 alkyl and n is from 1 to 8.
Preferred compounds of the invention are those having the general formula (II), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; 
wherein;
R22 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, xe2x80x94F, xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94Oxe2x80x94CH3;
xe2x80x94(L4)xe2x80x94 is a divalent group selected from; 
where R40, R41, R42, and R43 are each independently selected from hydrogen or C1-C8 alkyl.
R16 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio C1-C8 haloalkyl, C1-C8 hydroxyalkyl, and halo.
R13 is selected from hydrogen and C1-C8 alkyl, C1-C8 alkoxy, xe2x80x94Sxe2x80x94(C1-C8 alkyl), C1-C8 haloalkyl, C1-C8, phenyl, halophenyl, hydroxyalkyl, and halo, and t is an integer from 0 to 5.
A preferred compound (and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof) which is illustrative of the compounds of the invention is as follows:

The salts of the above indole compounds represented by formulae (I) and (II) are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, the (acidic group) of the substituent R4 of Formula I may be selected as xe2x80x94CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-Chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).
Method of Making the Compounds of the Invention
The synthesis of the indole compounds of the invention (viz., Compounds of Formulae I and II) can be accomplished by well known methods as recorded in the chemical literature. In particular, the indole starting materials may be prepared by the synthesis schemes taught in U.S. Pat. No. 5,654,326; the disclosure of which is incorporated herein by reference. Procedures useful for the synthesis of the starting material are shown in the Scheme below: 
To obtain the 3-ureido-1H-indole compounds (and other substituted compounds) substituted in the 4-position with an (acidic group) linked through an oxygen atom, the reactions outlined in the scheme supra, are used (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M. Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B. Repke, Michel Souchet, Synthesis, 1991, 871-878, the disclosures of which are incorporated herein by reference). The starting material ortho-nitrotoluene, 1, is readily reduced to 2-methyl,3-metoxyaniline, 2. Reduction of 1 is by the catalytic hydrogenation of the corresponding nitrotoluene using palladium on carbon as catalyst. The reduction can be carried out in ethanol or tetrahydrofuran (THF) or a combination of both, using a low pressure of hydrogen. The aniline, 2, obtained, is converted to the N-tert-butyloxycarbonyl derivative, 3, in good yield, on heating with di-tert-butyl dicarbonate in THF at reflux temperature. The dilithium salt of the dianion of 3 is generated at xe2x88x9240 to xe2x88x9220xc2x0 C. in THF using sec-butyllithium and reacted with the appropriately substituted N-methoxy-N-methylalkanamide to form the ketone 4. This product (4) may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 1,3-unsubstituted indole 5. The 1,3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature. (20-25xc2x0 C.) for 0.5-1.0 hour. The resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0-100xc2x0 C., usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6. This indole, 6, is O-demethylated by stirring with boron tribromide in methylene chloride for approximately 5 hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res., 1977, 12, 176, the disclosure of which is incorporated herein by reference). The 4-hydroxyindole, 7, is alkylated with an alpha bromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydride as a base, with reactions conditions similar to that described for the conversion of 5 to 6. The xcex1-((indol-4-yl)oxy)alkanoic acid ester, 8, is reacted with bis(2,2,2-trichloroethyl)azodicarboxylate in diethylether to give adduct 9. The adduct 9, was dissolved in tetrahydrofuran and reacted with zinc and glacial acetic acid, followed by treatment with excess trimethylsilylisocyanate to give the urea compound 10. This product, 10, is hydrolyzed using 1N sodium hydroxide in methanol. The final 3-ureido-indole compound, 11, is isolated either as the free carboxylic acid or as its sodium salt or in both forms.
Alternatively, other electrophiles may be substituted for trimethylsilylisocyanate to provide intermediates useful for conversion to novel inhibitors. These other electrophiles include, but are not limited to, acid anhydrides, ethyl oxalyl chloride, and ethoxycarbonylisothiocyanate. These agents react with the 3-aminoindole that results from the reduction of compound 9 as described above using zinc and acetic acid.
Compounds substituted at the 5 position of the indole nucleus with an (acidic group) may be prepared by methods and starting materials shown in schemes 2 and 3 of U.S. Pat. No. 5,654,326; the disclosure of which is incorporated herein by reference.
The thioureido analogs of the compounds of this invention can be made by substituting ethoxycarbonylisothiocyanate for trimethylsilylisocyanate to produce an intermediate compound which can be hydrolyzed to the thioureido-indole analog of compound 11. The thioureido compounds can also be isolated as the free acid or as its sodium salt.
Methods of Using the Compounds of the Invention
The indole compounds described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with an therapeutically effective amount of indole compounds corresponding to Formulae (I) or (II) as described herein including salt or a prodrug derivative thereof.
Another aspect of this invention is a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, panceatitis, trauma, asthma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose of the indole compound of the invention (see, formula I and II).
As previously noted the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid. By the term, xe2x80x9cinhibitingxe2x80x9d is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
Preferably compounds of the invention (per Formulae I or II) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the indole compound of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
In making the compositions of the present invention, the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.
For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
The Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d, refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Hard gelatin capsules are prepared using the following ingredients:
A tablet is prepared using the ingredients below:
The components are blended and compressed to form tablets each weighing 665 mg
An aerosol solution is prepared containing the following components:
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
Tablets, each containing 60 mg of Active ingredient, are made as follows:
The Active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules, each containing 80 mg of Active ingredient, are made as follows:
The Active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Suppositories, each containing 225 mg of Active ingredient, are made as follows:
The Active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Suspensions, each containing 50 mg of Active ingredient per 5 ml dose, are made as follows:
The Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
An intravenous formulation may be prepared as follows:
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.